Cheson et al. Blood Cancer Journal (2021) 11:68 https://doi.org/10.1038/s41408-021-00456-w Blood Cancer Journal

REVIEW ARTICLE Open Access Diffuse large B-cell : new targets and novel therapies Bruce D. Cheson 1, Grzegorz Nowakowski 2 and Gilles Salles3

Abstract Newer, more effective and non-cytotoxic therapies are an unmet need for patients with diffuse large B-cell lymphoma (DLBCL) and other B-cell malignancies. Recently approved agents include polatuzumab with bendamustine and , selinexor, and tafasitamab plus . Three CAR-T cell products are currently approved by the FDA, with others in clinical trials. Additional agents in development include bispecific antibodies and antibody drug conjugates. Combinations of targeted therapies should lead to further improvement in the outcome of patients with B-cell malignancies.

Introduction drug conjugate (Pola) with bend- The non-Hodgkin (NHL) are a diverse amustine and rituximab (Pola-BR)4; the oral nuclear group of malignancies about 80% of which are of B-cell transport (XPO1) inhibitor selinexor5; and, most recently origin (B-NHL). B-NHL vary in their presentation, clinical the combination of the anti-CD19 features, prognosis, and response to treatment. The most tafasitamab with the immunomodulatory agent lenalido- common histologic subtype is diffuse large B-cell lym- mide6. In addition are the first two CART-cell products 7 8

1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; phoma (DLBCL) accounting for about a third of cases in axicabtagene ciloleucel and tisagenlecleucel . Other the United States, followed by follicular lymphoma which drugs in development that target CD20 include the bis- represents about a quarter1. The other histologies are pecific T-cell engagers (e.g., mosunetuzumab9, glofita- much less common. About 60% of DLBCL are cured with mab10, epcoritamab11, and odronextamab12). Each of regimens such as rituximab, cyclophosphamide, Adria- these has exhibited promising early data, including in mycin, vincristine, and prednisone (R-CHOP)2. However, patients who have progressed following CAR-T therapy12. most patients who relapse following or are refractory to Polatuzumab vedotin is an antibody-drug conjugate that initial therapy succumb to their disease3. New drug targets CD79b and delivers the microtubule inhibitor development over the past decade has appropriately monomethyl auristatin E (MMAE). Polatuzumab vedotin ignored cytotoxic drugs and focused on was studied in a phase I, dose escalation trial in 95 patients agents that target the cell surface, internal pathways, and with NHL or CLL13. The primary endpoints were to the microenvironment. The chimeric anti-CD20 mono- determine the safety and tolerability, the maximum tol- clonal rituximab revolutionized the therapy of B-NHL, erated dose (MTD), and the recommended phase II dose. prolonging survival in most subtypes. However, resistance In the lymphoma patients, the MTD was 2.4 mg/kg as a eventually develops and other strategies directed at other single agent and in combination with rituximab. Grade 3-4 targets are needed. adverse events were reported in 58% of patients, most Recently, several innovative treatments have been commonly neutropenia (40%), with peripheral sensory approved by the FDA including the anti-CD79b antibody neuropathy in 9%. Responses were reported in 54.8% of the NHL patients. The drug was too toxic and had limited activity to be further pursued in CLL. Pola-BR received Correspondence: Bruce D. Cheson ([email protected]) accelerated approval for R/R DLBCL after two prior regi- 1Lymphoma Research Foundation, New York, NY, USA 2Mayo Clinic Foundation, Rochester, MN, USA mens (one prior in the European Union) on the basis of a Full list of author information is available at the end of the article

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Table 1 Tafasitamab monotherapy vs L-mind regimen in NHL.

Number of Overall Complete Median PFS Median DOR Reference patients response rate response rate (months) (months)

Tafasitamab single agent 35 (DLBCL) 26% 6% 2.7 20.1 Jurczak22 34 (FL) 29% 9% 8.8 Not reached Lenalidomide 76 (FL) 34.2% 13.2% 4.0 6.6 Nowakowski25 single agent Tafasitamab and 81 (DLBCL) 60% 42.5% 12.1 21.7 Salles6 lenalidomide

DLBCL diffuse large B-cell lymphoma, FL follicular lymphoma, PFS progression-free survival, DOR duration of response. randomized trial comparing Pola-BR with BR, with 40 subsequent analysis including 134 patients, those <65 patients per arm in which Pola-BR achieved a higher years had an ORR of 36.5 vs 24.4% for the older patients, complete remission (CR) rate (40.0 vs 17.5%, p < .026) and CRs 17.3 and 11%, and median duration of response a longer progression-free survival (PFS) (9.5 months vs (DOR) of 9.7 and 9.2 months, respectively. 3.7 months (p = .001) and overall survival (OS) (12.4 vs There have been concerns of a potential favorable 4.7 months, p = .002). (Table 1) However, Pola-BR was selection bias in the SADAL trial in that patients could associated with more grade 3-4 neutropenia, anemia, and not have had primary refractory disease, and those with a thrombocytopenia as well as grade 1–2 peripheral previous CR or partial remission (PR) to their prior line of neuropathy4. therapy were required to wait 60 days from that treatment Selinexor is an inhibitor of exportin 1 (XPO1), the to initiate selinexor, and 98 days for those with refractory major nuclear export protein for a number of tumor disease15. The actual time from progression of disease to suppressor genes and proto-oncogenes. Elevated XPO1 selinexor therapy was 1.5 months and 3.3 months, expression inactivates tumor suppressor proteins by respectively. However, patients in the SADAL study were mislocalization. Selinexor is a specific inhibitor of XPO1, comparable to typical patients given the patient age, it reactivates tumor suppressor proteins and blocks proto- amount of prior therapy. Moreover, 30% had progressed oncogene translation, DNA damage repair. The initial after an autologous stem cell transplant and 72% were phase I trial included 79 patients with NHL, 43 of which refractory to their immediately prior treatment regimen. had relapse or refractory DLBCL14. The most common In addition, the median time from disease progression adverse events included thrombocytopenia in 47%, neu- from the last prior therapy was 59 days in the selinexor tropenia in 32% and fatigue in 11%, with hyponatremia in responders compared with 52 days in the non-responders, 10%. In DLBCL, the ORR was 32% with CR in 10% and demonstrating that response did not correlate with time mDOR of 12.8 months. Activity was also noted in small since last therapy. numbers of patients with follicular lymphoma, CLL, Richter transformation, mantle cell and T-cell lympho- Targeting CD19 mas. The recommended phase 2 dose was 60 mg orally Another potential target is the CD19 antigen. CD19 is a twice weekly. Selinexor received accelerated approval for 95 kd, type I, transmembane glycoprotein. Expression of R/R or transformed DLBCL following two prior regimens CD19 is specific to B-lymphocytes and follicular dendritic on the basis of the SADAL single arm trial in patients with cells on which it is ubiquitous. Expression of CD19 on de novo or transformed DLBCL not considered eligible cells of B-lineage can be through the various stages of for autologous stem cell transplantation (ASCT) or post- differentiation from pre-B cells until plasma cells. CD19 ASCT5. These 134 patients had a median age of 67 years, functions as a positive regulator of B-cell receptor (BCR) median of two prior regimens, with 53% progressing signaling and is critical for B-cell development, and, in within a year of their first therapy for DLBCL. This oral mice the ability to mount an immune response to mito- agent achieved an ORR of 28% including 13% CRs and gens, and the production of serum immunoglobulins16. with a median duration of response of 9.3 months, but CD19 is present on malignant cells from the majority of was 23 months for the CRs. At the 60 mg twice weekly patients with NHL, acute lymphoblastic (ALL) dose used in this study, and with intensive anti-emetic and chronic lymphocytic leukemia (CLL). While CD20 support, the drug was well tolerated. The most common has a higher average density of surface molecules per toxicity was fatigue in 63%, which was grade 3 or 4 in 15%. tumor cell, CD19 expression is more homogenous and is Other grade 3–4 toxicities were uncommon. In a preserved in small CD20-negative tumor subsets and after

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Fig. 1 Mechanism of action of tafasitamab and lenalidomide. Tafasitamab has been Fc enhanced to increase antibody-dependent cellular cytotoxicity (ADCC) which augments interactions with natural killer (NK) cells activated and expanded by lenalidomide, antibody-dependent cellular phagocytosis (ADCP) to enhance interactions with macrophages, and direct cell death. anti-CD20 targeted therapy. Thus, CD19 serves as an Tafasitamab attractive target for lymphoma therapies. Tafasitamab is an Fc enhanced, humanized anti-CD19 Agents currently in development that target CD19 IgG1/IgG2 monoclonal antibody that was engineered to include tafasitamab, antibody drug conjugates such as have increased antibody dependent cellular cytotoxicity loncastuximab tesirine17, bispecific T-cell engagers, and (ADCC) and antibody dependent cellular phagocytosis CART-cell products including lisocaptagene maraleucel, (ADCP) with increased cell killing (Fig. 1). The activity of which was recently FDA approved18. Loncastuximab monoclonal antibodies is dependent on interactions with teserine is an antibody-drug conjugate comprised of a FcγRII, FcγRIII, and FcγRI receptors on effector cells. humanized anti-CD19 monoclonal antibody conjugated Natural killer (NK) cells solely express the FcγRIIIa to SG3199, a pyrrolobenzodiazepine dimer toxin. In the receptor. The majority of monoclonal antibodies in clin- phase I17, 88 patients with relapsed or refractory NHL and ical use, such as rituximab, require an interaction between a median of three prior regimens were treated with lon- their Fc domain and FcγRIIIa receptor on NK cells for castuximab teserine at doses escalating from 15–200 µg/ their potency. Tafasitamab has an Fc variant with a two- kg. The most common treatment emergent adverse events amino acid substitution at S239D and I332E which (TEAEs) included hematologic abnormalities, fatigue, increases its affinity to FcγR. The remaining protein liver chemistry elevations, nausea, rash, and dyspnea. At sequence of tafasitamab is identical to the IgG1 subclass doses of >150 µg/kg, the overall response rate was 59.4%, of monoclonal antibodies in the Fab and hinge regions including 40.6% CRs. In the subsequent final report and identical to the IgG2 subclass of monoclonal anti- including the dose expansion cohort19. one hundred and bodies in the CH2 and CH3 domains. eighty-three patients were included, with the expansion Tafasitamab has demonstrated additive or synergistic patients treated at either >120 µg/kg or >150 µg/kg. An activity in vitro with a number of chemotherapy agents MTD was not reached, but >150 µg/kg was chosen as the including bendamustine, fludarabine, rituximab, and RP2 dose. The most common TEAEs included febrile . neutropenia, fever, pleural effusion, dyspnea, and sepsis. Thirty-five (19.1%) patients experienced TEAEs with a Phase I study fatal outcome during the study, most commonly (20/35) In an initial phase I trial, tafasitamab was administered due to progression of underlying NHL. Six were con- to 27 patients with CLL at doses escalating from sidered treatment related, all of which were infections. 0.3–12 mg/kg, for nine infusions on days 1, 4, 8, 15, and Peripheral edema, pericardial or pleural effusions, and 22 of cycle 1 and days 1, 8, 15, and 22 of cycle 2. Following ascites were common and problematic, and elevated liver the two cycles, patients without progressive disease were chemistries were common. For the DLBCL cohort, the allowed to continue tafasitamab every 28 days for four ORR was 42.3%, with 23.4% CR; the median DOR was not additional infusions20. After demonstrating excellent tol- reached, and the PFS was only 2.8 months. erability, an expansion cohort was treated at 12 mg/kg. All

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patients experienced at least one TEAE, 24 of which were Phase II studies in non-hodgkin lymphoma thought possibly related to the study drug. Grade 3 or 4 Tafasitamab has been studied most extensively in NHL. toxicities included neutropenia (11%) (including a DLT of The first phase II trial involved 92 patients with various grade 4 neutropenia), thrombocytopenia (7.4%), elevated histologies of NHL including 35 DLBCL, 34 FL, 12 MCL, aspartate aminotransferase (3.7%), and tumor lysis syn- and 11 other indolent non-Hodgkin lymphoma (iNHL)22. drome (3.7%). Clinical responses occurred in 66.7% with Tafasitamab was administered at a dose of 12 mg/kg on day 29.8% responding by CT criteria. 1, 8, 15, and 22 of cycles 1 and 2, then every 2 weeks Pharmacokinetic studies were performed on 25 patients onward, and patients who achieved at least a PR were eli- and showed a two compartment model. The clearance gible to continue treatment until intolerance or progression and volume of distribution were similar to other full of disease. The ORR in relapsed/refractory DLBCL, FL, and length monoclonal antibodies with a maximum con- other iNHL was 26, 29, and 27%, respectively (Table 1). Of centration (Cmax) increasing in a somewhat less than a six patients with mantle cell lymphoma, there were no dose-proportional manner supporting that distribution responses and this cohort was terminated. The most com- was limited to the systemic circulation. The clearance and monly reported TEAEs were IRR and neutropenia, both half-life were not dose dependent. There was a trend of occurring in 12% of patients. Respiratory tract infection and accumulation in concentration with each infusion headache were reported in 11% each. The most common achieving a plateau state by infusion 9. In the studied grade 3 or higher adverse event was neutropenia (9%) which range from 3–12 mg, the drug half-life averaged 13.5 days mainly occurred during the first two cycles, with recovery allowing dosing intervals of 1 to 3 weeks. within 1 week (Table 3). The incidence of serious adverse events (SAEs) in the study was 30%; however, in only four patients (4%) was there a suspected relationship to tafasi- Phase II studies in CLL tamab. Two SAEs occurred in patients with DLBCL (febrile The phase I data supported the COSMOS study of neutropenia and genital herpes) and two with FL (dyspnea tafasitamab in patients with CLL and small lymphocytic and myelodysplastic syndrome). There were no treatment lymphoma (SLL)—who had progressed following a Bru- related deaths. ton tyrosine kinase (BTK) inhibitor21. Therapy involved treatment with tafasitamab and either the PI3k inhibitor Combination regimens idelalisib (Cohort A) or (Cohort B). Tafasita- Supported by the modest single agent response rate of mab (12 mg/kg) was administered in 28-day cycles. In tafasitamab in DLBCL, combinations with other agents cycles 1–3 tafasitamab was infused on day 1, day 8, day 15, were developed. To date, the most promising of partners and day 22 with an additional loading dose on day 4 of has been the immunomodulatory drug, lenalidomide. The cycle 1. In subsequent cycles, tafasitamab was adminis- rationale is that the antibody augments cellular immunity tered on days 1 and 15 for cycle 4–6 monthly cycles, and against the lymphoma cell target. The Fc enhanced por- only on day 1 from cycle 7 to 24 or until disease pro- tion of tafasitamab has increased affinity to Fcγ receptors gression or intolerance. Cohort A enrolled 11 patients such as FcγRIIIa. These FcγRIIIa receptors, present on who received a median of five prior lines of therapy, more immune effector cells such as NK cells, mediate the than half of which had a complex karyotype or del17p/ ADCC response. Lower PB NK cell count has been TP53. The most common grade 3 or higher TEAEs were associated with poorer clinical outcomes in patients with neutropenia (46%), anemia (27%), thrombocytopenia DLBCL supporting an essential role of NK cells in ADCC. (27%), pneumonia (27%), and elevated transaminases In addition, the antibody induces ADCP, augmenting (18%). Fatal heart failure occurred in one patient. The macrophage cell killing. Lenalidomide has been well stu- ORR in Cohort A was 90.9% with 9.1% CRs. Two of eight died in lymphoma both as a single agent and in combi- patients who were assessed for minimal residual disease nations. In vitro studies demonstrated that NK-cell (MRD) status were undetectable in the peripheral blood mediated ADCC with tafasitamab was further enhanced (PB), and one of three in the bone marrow (BM). Cohort B by lenalidomide. included 13 patients who had received a median of three These observations led to the L-MIND study, a phase II prior lines of treatment, more than 90% of which had a trial of the combination of lenalidomide and tafasitamab complex karyotype and 69% unmutated IGHV status. The (Fig. 2)6. Eligibility required age of at least 18 years with most common grade 3 or higher TEAEs were neutropenia relapsed or refractory (but not primary refractory) DLBCL (46%), hypophosphatemia (31%), and infusion related and ECOG performance status of 0–2. Patients could not reactions (IRR) (15%). The ORR was 76.9% with 23.1% be considered eligible for ASCT by their primary physi- CRs. Of the seven patients assessed for MRD status, six cian on the basis of age or the presence of comorbidities. became undetectable in the PB, and two of four patients A small subset entered the trial after refusal of ASCT. in the BM. Tafasitamab was administered at a dose of 12 mg/kg iv on

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Fig. 2 Schema of the L-MIND regimen. Patients receive the combination of tafasitamab and lenalidomide for 12 cycles, and those with at least stable disease can continue on single agent tafasitamab until disease progression or intolerance. days 1, 4, 8, 15, and 22 for cycle 1, days 1, 8, 15, and 22 for In updated results, as of November 2019, the ORR was cycles 2–3, and days 1 and 15 for subsequent cycles. 58.8% with 41.3% CRs23. The median PFS was 16.2 months Lenalidomide was dosed at 25 mg a day, day 1–21 of each with a median survival of 31.6 months (Fig. 3). With at least 28-day cycle, higher than the 20 mg dose used in the 24 months of follow-up, the median DOR was 34.6 months rituximab plus lenalidomide regimen. Patients with stable (Fig. 4). Of note was that the median DOR was not reached disease or better after 12 monthly cycles were eligible to for the CRs, but was 5.6 months for the PRs, confirming the continue tafasitamab as a single agent until disease pro- importance of achieving a CR. At the time of this publica- gression or intolerance. The primary endpoint was ORR, tion there were 22 patients still on therapy. with secondary endpoints including PFS, DOR, safety and This regimen was well-tolerated with the major adverse a number of exploratory biomarker studies. effects being neutropenia: grade 3 and 4 in 27 and 21%, There were 81 patients accrued to the study. Patient respectively, but without infections. Grade 3 thrombocy- characteristics included a median age of 72 (41–86) years. topenia was reported in 17%. Non-hematologic toxicities Fifty-four percent were male and 75% had stage III or IV included rash (grade 1–2 in 27%, grade 3 in 9%); grade disease. IPI 0–2 were in 49% and an elevated LDH was 1–2 diarrhea in 32%, but grade 3 in only 1%; other toxi- noted in 56%. These patients had limited adverse features. cities occurring in at least 20% of patients included Whereas they had received a median of two prior lines of asthenia (21%), cough (21%), peripheral edema (22%), therapy, 49% only had one prior and 43% two prior fever (20%), and decreased appetite (20%); however, grade therapies. Only 15 patients (18%) were considered to have 3 or worse toxicities were uncommon (Table 2). Treat- primary refractory disease. Such patients were not initially ment related SAE occurred in 18.5% of patients with 10% considered eligible for the study; however, the definition experiencing infections and 5% with febrile neutropenia. of “primary refractory” changed during the conduct of the There were four treatment related deaths (sudden death, trial from progression within 3 months to progression respiratory failure, cerebrovascular accident, progressive within 6 months and the 15 patients had been within the multifocal leukoencephalopathy), none thought to be 3–6 month window. In addition, 44% were considered related to study drugs. The marked reduction in toxicity refractory to their prior line of therapy. Eleven percent with the prolonged tafasitamab as a single agent suggests underwent a prior stem cell transplant. Cell of origin was that the toxicity during induction was primarily the result germinal center B-cell (GCB) in 46%, non-GCB in 25%, of lenalidomide. Despite the 25 mg starting dose of lena- and unknown in 30%. Of note is that CART-cell patients lidomide, 80% of patients were able to remain on at least are also a selected population, and the 40% long-term 20 mg. About half the patients received growth factor duration of response is not dissimilar from that reported support at the discretion of the treating physician in order with either autologous stem cell transplant or L-MIND in to maintain dose intensity, which is considered important transplant ineligible patients. for the efficacy of the regimen.

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Fig. 3 Progression-free survival in the L-MIND Study (courtesy of Morphosys). The median PFS is 16.2 months (95% CI: 6.3-NR).

Fig. 4 Duration of response in the L-MIND study (courtesy of Morphosys). DOR correlates with response in DLBCL with NR in those with a CR and only 5.6 months for those with a PR.

In the L-MIND study, grade 3 and 4 neutropenia were the starting dose. The routine prophylactic use of a reported in 27 and 21%, respectively; however, febrile growth factor is not recommended; however, such an neutropenia in only 10 and 2%, respectively. Neutropenia agent should be considered in the setting of grade 3 or 4 was managed by granulocyte colony-stimulating factor in neutropenia lasting >7 days or in patients with recurrent 44% of patients, including 81% of those with grade 3 or 4 neutropenia to maintain the lenalidomide dose. neutropenia. The majority of these cases returned to The efficacy of L-MIND appears to be superior to the normal neutrophil count within a week. 29% ORR previously reported with tafasitamab mono- Management of neutropenia with L-MIND is similar to therapy (Table 1). However, at the request of the FDA, the the published recommendations for ritiuximab plus RE-MIND study was designed as a non-interventional lenalidamide (R2)24. When neutrophils fall below 1000/µl data comparison of patients treated with L-MIND with for at least 7 days or below 1000/µl in the setting of a fever those treated with single agent lenalidomide who were >38.5 °C, or <500/µl, lenalidomide should be interrupted matched for nine relevant clinical and laboratory features; and blood counts checked weekly. When neutrophils age, stage, refractoriness to last line of therapy, number of return to >1000/µl, resume at a dose 5 mg/day less than prior therapies, history of prior refractoriness, prior

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Table 2 Adverse events of grade 3 or higher encountered Whether L-MIND is superior to R2 in DLBCL is in NHL patients in phase II studies. unknown as there have been no direct comparisons. Wang et al. reported on 32 patients with relapsed or Events Tafasitamab Tafasitamab and refractory DLBCL, transformed or grade 3 follicular single agenta lenalidomideb lymphoma at a median age of 65 years and with a median 26 Neutropenia 9% 48% of three prior lines of therapy . The ORR was 33% with 22% CR, a median PFS of 2.8 months and a median OS of Thrombocytopenia 4% 17% 10.2 months. For the DLBCL subset (n = 32), the ORR Anemia 3% 7% was 28% including 22% CRs. Zinzani et al.27 reported a Febrile neutropenia - 2% series of 23 elderly patients with relapsed or refractory Dyspnea 4% - disease. The ORR was 35% with 30% CR, a 1-year disease- free survival rate of 34.8% and an 18 month OS of 55.1%. Pneumonia 3% 6% Despite differences in patients, the results with L-MIND Fatigue 2% 2% appear superior to either of these studies. Hypokalemia 2% 1% Other tafasitamab combinations are in development. fi Rashes - 9% The B-MIND study is the con rmatory trial for L-MIND and it is an ongoing comparison between bendamustine Hypokalemia - 6% and rituximab vs bendamustine tafasitamab in relapsed Urinary tract infection - 5% and refractory DLBCL. FIRST-MIND is a phase 1b study Hypertension - 4% exploring the relative tolerability of R-CHOP-tafasitamab + Pulmonary embolism and -4% vs R-CHOP-tafasitabmab lenalidomide. The more deep vein thrombosis favorable regimen will likely be compared with R-CHOP in a phase III trial in previously untreated DLBCL. Atrial fibrillation - 3% Upper respiratory tract -2% Toxicities of tafasitamab infection Tafasitamab as a single agent and in combination with Congestive heart failure - 2% lenalidomide is generally well tolerated. The most com- Increased transaminases - 2% mon adverse events are listed in Table 2 which suggests that most of the toxicities in the L-MIND study were Renal failure - 2% related to the lenalidomide. Back pain - 2% Asthenia - 2% Tafasitamab administration and dose modifications aEncountered in two or more patients. bIn at least 2% of the patients. Patient treated with tafasitamab should receive pre- with acetaminophen, histamine H2 receptor antagonists and/or glucocorticoids. Premedication should ASCT, neutropenia, anemia, and elevated LDH25. The be administered 30 min to 2 h prior to starting tafasitamab primary endpoint was best ORR determined by the administration. Subsequent premedication is optional for investigator. There were 490 patients identified with patients who do not experience an infusion-related reac- lenalidomide therapy alone of which 76 matched with 76 tion during the first three infusions. However, patients of those patients from the L-MIND study. The ORR and who continue to experience infusion-related reactions CR rates with L-MIND were 67.1% and 39.5%, respec- should receive premedication before each subsequent tively, and for lenalidomide monotherapy 34.2% and infusion. The dose of tafasitamab is 12 mg/kg intrave- 13.2%, respectively (p < 0.0001). The PFS was 12.1 months nously days 1, 4, 8, 15, and 22 of cycle 1; days 1, 8, 15, and vs 4 months (p = .0002; HR 95% CI 0.307–0.698) and 22 of cycles 2 and 3; days 1 and 15 of cycles 4–12 and for overall survival was also significantly longer at not subsequent cycles for patients whose response is at least reached vs 9.4 months for the L-MIND regimen vs lena- stable disease until progression of disease or intolerance. lidomide monotherapy, respectively (p = .0026) (HR 95% The first infusion should be administered at a rate of CI, 0.317–0.785) (Table 1). RE-MIND2 is being planned 70 mL/h for the first 30 min, then, the rate can be in which the data with tafasitamab and lenalidomide will increased, in the absence of an infusion reaction, so that be compared in a similar fashion with patients treated the infusion is administered within 1.5 to 2.5 h. All sub- with a variety of other options. sequent infusions can be delivered within 1.5 to 2 h. Based on these data, L-MIND was granted accelerated Dose modification recommendations for hematologic approval by the FDA on August 3, 2020. toxicity are outlined in Table 3.

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Table 3 Dose modifications for tafasitamab and lenalidomide hematologic toxicities.

Event Dose modification

Platelet count ≤50,000/µl Hold tafasitamab and lenalidomide and monitor counts weekly until platelet count is ≥50,000/µl Neutrophil count ≤1000/µl for at least 7 days or febrile neutropenia or Hold tafasitamab and lenalidomide and monitor counts weekly until neutrophil count ≤500/µl neutrophil count is ≥1000/µl

Table 4 Response and outcomes results for regimens for the treatment of relapsed and refractory DLBCL.

Efficacy metric Selinexor (n = 134) Pola-BR (n = 40) L-MIND (n = 81) R-GemOX (n = 49) R-GDP (n = 52) R2 (n = 32)

ORR, % 29 45 57.5 61 63 28 CR, % 13 40 40 44 31 22 mDOR (mo) 9.3 12.6 34.6 10 NR 6 mPFS (mo) 2.6 9.5 12.1 5 3 yr–31% 2.8 mOS (mo) 9.0 12.4 31.6 11 3 yr–66% 10.2

Future directions As CD19 is expressed on virtually all B-cell malig- Several active targeted therapies have been approved by nancies, a logical step is to test tafasitamab alone or with the FDA for patients with relapsed or refractory DLBCL, lenalidomide in other histologies, notably FL and marginal with numerous others in development. The L-MIND zone lymphoma (MZL). Since early studies did not sug- regimen is the first therapy approved for second and gest activity in MCL, further pursuit is of lower priority. subsequent lines of therapy patients not considered can- The rituximab/lenalidomide (R2) regimen has been shown didates for ASCT. As noted above, studies are ongoing to be effective in the relapsed/refractory and front-line and planned to determine the role of tafasitamab as part settings. Whether substituting tafasitamab for rituximab of initial therapy for patients with this histology. Patients or adding the two antibodies are two approaches that with DLBCL are often elderly with comorbidities. Com- should be considered. Combinations of monoclonal bining L-MIND with mini-CHOP or comparing L-MIND antibodies in lymphoid malignancies has been shown to + rituximab with mini-CHOP are questions worthy of be effective in earlier studies. Such regimens could not study in such a population. only be studied in the relapsed refractory setting, as in the Patients with relapsed or refractory disease have pro- AUGMENT study, but also in the front-line setting. Other gressed after anti-CD20 therapy. Thus, switching to combinations with PI3k or BTK inhibitors may be worthy CD19-direted therapy may improve patient outcome. of testing in appropriate histologies. Future directions Incorporating tafasitamab into a pre-ASCT regimen is a include combinations with other agents or substitution question worth study. for rituximab in patients previously treated with the anti- Concerns have been expressed that using an anti-CD19 CD20 monoclonal antibody. agent may compromise subsequent CART-cell therapy. Tafasitamab may also serve as a backbone for the However, levels of CD19 are maintained following tafa- development of novel strategies for patients with other sitamab therapy and anecdotes suggest successful cellular histologies of NHL. therapy in patients previously treated with L-MIND. Having an increasing number of active therapies for CART-cell therapy is an extremely promising therapy for DLBCL raises a number of issues. First is how best to DLBCL, MCL, and FL. However, the majority of patients sequence them. At present, L-MIND is the only therapy do not benefit and face disease progression. Tafasitamab- approved for patients failing a single prior systemic regi- based therapy should be tested in this setting, except in men. For patients progressing after this regimen and not those patients whose cells no longer express CD19. suitable for CART therapy, the decision is between seli- Based on their mechanism of action, the activity of nexor and Pola-BR (Table 4). The former has an advan- targeted agents as anti-CD47 antibodies, check point tage for ease of administration and a favorable safety inhibitors, or bispecific T-cell engagers, might be aug- profile. Whereas the latter achieves a higher CR rate and mented by L-MIND. longer PFS, the DOR rates were comparable. Moreover,

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an advantage for selinexor is its ease of incorporation into are underway, identification of biomarkers are essential to combination strategies, many of which are currently in help select individual patients for optimal therapies. Such development. novel chemo-free approaches will certainly lead to Thus, with the increasing availability and approval of improved outcomes for patients with DLBCL and other novel therapies for DLBCL, recommendations for an histologies of B-cell lymphomas. optimal paradigm is challenging and dynamic. At present, Author details the L-MIND regimen is the only FDA approved second- 1Lymphoma Research Foundation, New York, NY, USA. 2Mayo Clinic line therapy, although polatuzumab + BR has recently Foundation, Rochester, MN, USA. 3Lymphoma Service, Memorial Sloan- received compendium status. CART therapy is currently Kettering Cancer Center, New York, NY, USA approved in the third line; however, three ongoing trials Conflict of interest are evaluating this therapy in the second line (axicapta- B.D.C.—Advisory boards/consulting—Morphosys, Karyopharm, BMS/Celgene, gene ciloleucel, tisagenlecleucel, and lisocaptagene mar- Kite, Epizyme, Beigene, Symbio, TG Therapeutics; G.N.—Celgene/BMS, oleucel), and one in front-line, high-risk patients28. Thus, Morphosys, Curis, Seattle Genetics, Kymera, Kite, Ryvu; G.S.—Morphosys, Abbvie, Autolus, Beigene, BMS/Celgene, Genmab, Roche, Janssen, patients who are relapsed/refractory to R-CHOP are dis- Debiopharm, Milteniy, Novartis, Velosbio. tinguished by their eligibility for stem cell transplantation. For those who are not, L-MIND is the approved option. Therapies for the third line include CAR T for those who Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in are eligible and who have access to the procedure, or published maps and institutional affiliations. selinexor and poltazumab-BR; the oral administration and safety profile of the former are in its favor; however, the Received: 30 December 2020 Revised: 23 February 2021 Accepted: 3 March CR rate and PFS support the latter. Should loncastuximab 2021 teserine receive approval, its position in the paradigm will be determined by the line of treatment for which is indicated. How best to move these regimens earlier in the course References 1.Armitage,J.O.&Weisenburger,D.D.Newapproachtoclassifyingnon- of the disease where they are likely to be more effective is Hodgkin’s lymphomas: clinical features of the major histologic subtypes. J. Clin. an important consideration. 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